The present invention is generally in the area of methods and compositions to reduce restenosis after revascularization of diseased coronary, peripheral, and cerebral arteries, and stenosis or restenosis of surgically-placed bypass grafts or transplanted organs, specifically by local administration of an agent such as apolipoprotein A-I Milano alone or in combination with lipid formulations or other cholesterol lowering agents or lipid regulating agents.
Angioplasty, surgery and other vascular interventions are complicated by an accelerated arteriopathy characterized by rapid growth of cells into the lumen within a short period of time. This growth is often severe enough to jeopardize the blood flow to distal organs.
Vascular bypass surgery has been widely used to treat stenotic and occluded blood vessels, as when plaques develop on the surface of blood vessels in atherosclerosis. In bypass surgery, one or more healthy blood vessels are grafted into the stenotic/occluded vessels beyond the site of stenosis or occlusion to shunt blood around the stenotic or occluded vessel to re-establish a sufficient blood supply to the tissue whose blood supply is endangered by the stenosis or occlusion. This surgery often successfully revascularizes the endangered tissue.
Angioplasty has been developed as an alternative treatment to bypass surgery, especially in patients who have been diagnosed early in the development of stenosis or occlusion of blood vessels due to the abnormal laying down of plaque on the luminal wall of a blood vessel. Angioplasty typically involves guiding a catheter which is usually fitted with a balloon or expandable metal mesh to an artery region of stenosis or occlusion and the brief inflation, one or more times, of the balloon or wire mesh to push the obstructing intravascular material or plaque up against the endothelial wall of the vessel, thereby compressing and/or breaking apart the plaque and reestablishing blood flow. However, angioplasty treatment can injure the vessel, especially when the balloon is over inflated or the mesh overextended, causing a variety of undesirable results, such as denudation (removal) of the endothelial cell layer in the region of the angioplasty, dissection of part of the inner vessel wall from the remainder of the vessel with accompanying occlusion of the vessel, or rupture of the tunica intima layer of the vessel.
Injury of arteries in animals induces a process of vascular repair which eventually causes the artery to become narrowed. A thick new layer, or neointima, of smooth muscle cells and inflammatory cells grows within the blood vessel, encroaching on the lumen. This process in animals represents the process that occurs clinically after angioplasty, endovascular stent implantation, organ transplantation, or bypass surgery, which greatly limits the long term successes of these techniques for treating obstructive arterial disease. Animal models of arterial injury and neointimal hyperplasia have been used to study the cellular events which lead to restenosis in humans, to devise treatment strategies to suppress tissue growth in an attempt to reduce restenosis and enhance long term clinical results. Pigs are particularly useful as an animal model for restenosis in humans.
Attempts to limit stenosis or restenosis of blood vessels following revascularization have included administration of pharmacologic agents and technical approaches. No pharmaceutical agent has been clinically approved for the indication to prevent restenosis in humans. One technical approach, endovascular stent placement, has been shown to partially reduce restenosis in humans after coronary arterial intervention, as reported by Serruys, et al. N. E. J. Med. 1994; 331:489-495 and Fischman, et al. N. E. J. Med. 1994; 331:496-501. Nevertheless, stents themselves remain susceptible to significant restenosis in 20-30% of cases.
Increased knowledge of the mechanisms underlying vascular repair has led to innovative proposals for agents to limit accelerated arteriopathies. Circulatory leukocytes, including monocytes, are known to be among the very first cells recruited to blood vessels as atherosclerosis begins. Once within diseased arterial walls, these cells may engulf cholesterol and other lipids, and may also produce substances that attract other cells, cause other cells to proliferate, or degrade matrix components. Each of these secondary effects may in turn promote greater intimal thickening and more severe narrowing or occlusion of the arterial lumen. A similar role for leukocytes in restenosis after revascularization has not been proven. Although leukocyte activation has been connected to restenosis in humans (Pietersma, et al. Circulation 1995; 91:1320-1325; Mickelson, et al., 1996 JACC 28(2):345-353; Inoue, et al., 1996 JACC 28(5):1127-1133) broad inhibition of inflammation, for example with glucocorticoids, after revascularization has not reduced restenosis in humans (Pepine et al., Circulation 1990; 81:1753-1761). This observation is reminiscent of studies using both broadly active and very specifically targeted treatments for preventing restenosis. Broad treatments, for example with heparin, have been limited by systemic toxicities and dosing limitations. Specific treatments, for example with molecular strategies, have failed to inhibit all of the redundant cellular and molecular pathways which activate and potentiate the vascular repair process.
Ameli, et al., Circulation 90(4):1935-41 (1994) reported that several epidemiological studies have shown an inverse relation between high-density lipoprotein (HDL) cholesterol levels and coronary heart disease and a similar inverse relation between HDL and restenosis after coronary balloon angioplasty. They conducted a study to determine whether HDL directly influences neointima formation, investigating the effect of recombinant apoA-I Milano (apoA-IM, a variant of human apoA-I with Arg-173 to Cys substitution), on intimal thickening after balloon injury in cholesterol-fed rabbits. Rabbits received intravenous injections of 40 mg of apoA-IM linked to a phospholipid carrier on alternate days, beginning 5 days before and continuing for 5 days after balloon injury of femoral and iliac arteries (a total dosage of 200 mg/animal, or about 11.4 mg/kg/dose). Three weeks after balloon injury, apoA-IM-treated rabbits had significantly reduced intimal thickness compared with the two control groups. The intima-to-media ratio was also significantly reduced by apoA-IM by ANOVA compared with the two controls. The fraction of intimal lesion covered by macrophages, as identified by immunohistochemistry using a macrophage-specific monoclonal antibody, was significantly less in apoA-IM-treated rabbits compared with carrier-treated animals (25.3+/−17% versus 59.4+/−12.3%, P<0.005). Aortic cholesterol content, did not differ significantly between apoA-IM-treated animals and carrier alone-treated controls. Unfortunately, unlike in pigs where the lesions are more human like, results obtained in rabbits have not been predictive of results in humans.
Accordingly, there is a need for compositions and methods of promoting healing of vascular tissue and controlling vascular muscle cell proliferation (hyperplasia) to prevent restenosis of blood vessels after angioplasty, vascular bypass, organ transplantation, or vascular disease, with minimal risk of rapid reocclusion.
It is therefore an object of the present invention to provide a method and compositions to reduce restenosis after revascularization of diseased coronary, peripheral, and cerebral arteries and stenosis or restenosis of surgically-placed bypass grafts or transplanted organs.
It is a further object of the present invention to provide a method which is a simple and effective means of gene transfer.